Derivatives of 3beta-halo-17alpha-(carboxyethyl)-delta-androsten-17beta-ol-lactone and 3beta-halo-17alpha(carboxyvinyl)-delta-androsten-17beta-ol-lactone



finited rates Patent 3-,WL582 Patented Jan. 1, I963 lice DERIVATIVES F 3p-HALO 17oz (CARBOXYETH- YL)"A5'ANDRQSTEN1750L'LACTONE AND 3(3- HALO-I7a(CARBXYVINYL) A ANDRGSTEN- l7p-OL-LACTONE John A. Zderic, Palo Alto, (Ialifi, and ()tto Halpern and .Iose Iriarte, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed .Iau. 17, 1962, Ser. No. 166,951

20 Claims. (Cl. 260-239.57)

In the above formulas R represents hydrogen or methyl; X represents fluorine or chlorine, Y represents fluorine, chlorine or bromine; and Z may be a double bond or a saturated linkage.

The novel C6-unsubstituted compounds of the present invention are prepared by the process exemplified by the following equation:

In the above formulas R, Y and Z have the same meaning as previously set forth. In practicing the process outlined above, the starting compound which is a I7CL-(ZI- carboxyethyl or carboxyvinyl)-A -androstene-3fi,17fl-dio1- lactone derivative (I), is treated with a halogenating agent such as phosphorus pentabromide, phosphorus pentachloride or hydrogen fluoride in a solvent inert to the reagent, thus afi'ording the respective 3B-halo derivative (II).

The novel C-6-substituted compounds of the present invention may be produced by the process illustrated as follows:

O=(|3- O=C- 0 I R R. i

no no i O=C O= I 1 J 0 l R R. I

(VI) (v) Y- HO In the above formulas R, X and Y have the same meaning as heretofore set forth.

In practicing the process just outlined, the starting compound which is a 17a-(2'-carboxyethyl)-A -androstene- 35,1713-diol-1actone derivative (III) is treated with phenyl iodoso difluoride or dichloride to give the respective 50c, 6a-difiuoro or dichloro l7a-(2-carboxyethyl) -androstane- 36,1713-diol lactone (IV) which upon dehydrohalogenation with a suitable agent such as calcium carbonate in dimethyl formamide, yields the corresponding 6-halo-17c- (2-carboxyethyl)-A -androstene-3B,17a-diol-1actone (V). The latter compound upon halogenation of the 3p-hydroxyl with a suitable agent such as hydrogen fluoride, phosphorus pentachloride or phosphorus pentabromide, yields the respective 3,8-fiuoro, chloro or brorno-6-halo- 17a- (2'-carboxyethyl -A -androsten-17fl-ol-lactone (VI) The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention:

PREPARATION 1 A solution of 5 g. of 17a-(2'-carboxyethyl)-l9-nor A -androsten-17,B-ol-3-one lactone (Celia et al., J. Org. Chem. 24, 743 (1959)), in 50 cc. of acetic anhydride and 50 cc. of acetyl chloride was boiled for 4 hours under an atmosphere of nitrogen. The reaction mixture was then distilled almost to dryness, cooled, diluted with ether and the organic extract washed with water, then with 5% sodium bicarbonate solution and finally with water. There was thus obtained 3-acetoxy-l7a-(2'-carboxyethyl)-l9- nor-A -androstadien-l7/3-ol lactone.

Following the same procedure, 17a-(2'-carboxyvinyl)- 19-nor-A -androsten-17fi-ol-3-one lactone was treated (Cella et al. v. supra) thus yielding 3-acetoXy-l7a(2'- carboxyvinyl)-19-nor-A -anclrostadien-17p-ol lactone.

A solution of 4 g. of 3-acetoxy-l7a-(2-carboxyethyl)- 19-nor-A -androstadien-175-01 lactone in a mixture of 100 cc. of 95% ethanol and 35 cc. of tetrahydrofuran was cooled at C. and added dropwise, with occasional stirring over a 1 hour period, to a cold solution of 4 g. of sodium borohydride in 50 cc. of 80% ethanol, the reaction temperature not being allowed to exceed 5 C. After completion of addition, the solution was kept at 0-5 C. for 2 hours further; then 200 cc. of 10% sodiurn hydroxide was added and the solution boiled for minutes. Most of the solvent was removed in vacuo, the residue acidified with hydrochloric acid and the crystalline precipitate collected and washed. Recrystallization of the crude material from acetone furnished 17a- (2'-'carboxyethyl)-19-nor-A -androstene-35,175-diol lactone.

By the above procedure there was treated 3-acetoxy- 17u-(2'-c'arboxyvinyl)-l9-110r-A -androstadien 175 ol lactone to give 17a-(2-carboxyvinyl)-19-nor-A -androstene-35,l75-diol lactone.

Example I To a solution of 5 g. of l7u-(2'-carboxyethyl)-A androstene-35,l75-diol lactone (Cella et al. v. supra) in 10 0 cc. of benzene were added 5 g. of phosphorus pentachloride and the resulting mixture was refluxed for 1 hour in the absence of moisture. it was then cooled, poured into water; the benzene layer was washed with Water several times, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane yielded 35-chloro-l7ot-(2-carboxyethyl)-A -androsten-175-ol lactone.

In accordance with the foregoing technique there were treated: 17a. (2' carboxyethyl) 19 nor A androstene 35,175 diol lactone, 17a (2 carboxyvinyl)- 19-nor-A -androstene-35,175-diol lactone and 17OC-(2'-Ca1'- boxyvinyl) A androsten 35,175 diol lactone (Cella et al. v. supra) yielding correspondingly: 35-chloro-17a- (2' carboxyethyl) l9 nor A androsten 175 ol lactone, 35 chloro 17a (2 carboxyvinyl) 19 nor- 'A androsten 175 ol lactone, and 35 chloro 170c- (2'-carboxyvinyl)-A -androsten-175-ol lactone.

Example I] In a polyethylene flask, adapted with magnetic stirrer, there was dissolved 2.8 g. of 17ot-(2'-carboxyethyl)A androstene-35,175-diol lactone in cc. of methylene chloride, the solution was cooled to 0 C. and a solution of 12 g. of anhydrous hydrogen fluoride in 20 cc. of tetrahydrofuran cooled in a Dry-Ice acetone bath (-70 C.) was added over a period of 20 minutes with constant stirring. The mixture was stirred at a temperature lower than 10 C. for 6 additional hours, then neutralized by cautiously adding a 5% aqueous sodium bicarbonate solution and transferred to a separatory funnel. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate filtered and redissolved in hot ethyl acetate, the soluble material was filtered oli and the filtrate cooled whereby there crystallized -fiuoro-17u-(2-carboxyethyl)-A -androsten-175-ol lactone.

There were treated according to the above procedure: 170: (2 carboxyethyl) 19 nor A androstene 35,

I 175 diol lactone, 17oz (2' carboxyvinyl) 19 nor- A -androstene-35,175-diol 'lactone, and 17w(2-carboxyvinyl)-A -androstene-35,175-diol lactone thus giving respectively: 35-fluoro-17ot-(2'-carboxyethyl)-19-nor-/ -androsten-175-ol lactone, 35-fluoro-17a-(2'-carboxyvinyl)- 19-nor-A -androsten-175-o1 lactone, and 35-fiuoro-17a- (2-carboxyvinyl)-A -androsten-175-ol lactone.

Example III A mixture of 2.5 g. of 17o-(2'-earboxyethyl)-A -androsten-35,175-diol lactone, 1.05 mol. equivalents cf phenyl iodoso dichloride and cc. of chloroform was refluxed until the crystals of the reagent disappeared. The solvents were removed and the residue recrystallized from chloroform-ethyl acetate thus yielding 5 oc,6oc-dlChlOf0- a (2 carboxyethyl) androstane 35,175-diol lactone.

Following the same technique there was treated 170442- carboxyethyl) 19 nor A androstene 35,175 diol lactone thus affording 50:,6oc-(11Chl010-17cc-(2'-Ca1'b0Xyethyl) -19-nor-androstane-35,175-diol lactone.

Example IV 2 g. of 5a,6ot dichloro 17a (2 carboxyethyl)- androstane-35,175-diol lactone in 40 cc. of cold dimethylforrnamide was added over 15 minutes to a suspension of 5 g. of finely divided calcium carbonate in 15 cc. of refluxing dimethylforma-mide. The mixture was refluxed for 30 minutes further, cooled and filtered. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate and evaporated to dryness. Silica gel chromatography and recrystallization afforded 6-chloro-17a-(2-carboxyethyl)-A -androstene-35,175-diol lactone.

By the same procedure 5u,6e-dichloro-17a-(2-carboxyethyl) 19 nor A androstene 35,175 -diol lactone was converted to 6-chloro17ot-(2-carboxyethyl)-l9-nor- A -androstene-35,175-diol lactone.

Example V 17cc (2 carboxyethyl) A -androstene 35,175- dial lactone, 17oz (2' -carboxyethy1) 19 nor A -androstene-35,l75-diol lactone were treated following the procedure described in Example III, except that phenyl iodoso dichloride was substituted by phenyl iodoso difluoride thus giving respectively: 5a,6 -ditiuoro-l7a-(2- carboxyethyl) androstane 35,175 diol lactone and 5a,6a difiuoro 171x (2 carboxyethyl) 19 norandrostane-35,175-diol lactone.

Example V1 The two preceding compounds were treated following the procedure described in Example IV yielding correspondingly: 6 fluoro 17a (2 -carboxyethyl) A androstene 35,175 diol lactone, and 6 fluoro 17cc- (2' carboxyethyl) 19 nor A androstene 3 5,175- diol lactone.

Example VII 6 chloro 170a (2' carboxyethyl) A androstene- 35,175 diol lactone, 6 chloro 17m (2' carboxyethyl) 19 nor A androstene 35,175, diol lactone, 6 fluoro 17a. (2 carboxyethyl) 19 nor- A androstene 35,175 diol lactone, and 6 fluoro- 17a-(2-carboxyethy1) A androstene 35,175 diol lactone were treated following the procedure described in Example I, affording respectively: 35-6-dichloro-17a-(2- carboxyethyl) A androsten 175 ol lactone, 35,6-.

dichloro 17oz (2' carboxyethyl) 19 nor A androsten 175 ol lactone, 35 chloro 6 fluoro- 17m- (2' carboxyethyl) 19 -nor A androsten 175 o1 lactone and 35 chloro 6 fluoro 170a (2' carboxyethyl)-A -androstenl75-ol lactone.

Example VIII 6 chloro 17oz (2 -carboxyethyl) A androstene- 35,175 diol lactone, 6 chloro 170a (2 carboxyethyl) 19 nor A androstene 35,l75 diol lactone, 6 fluoro 17a (2 -carboxyethyl) 19 -nor A androstene-35,175-diol lactone, and 6-fluoro-l7a-(2 carboxyethyl) A androstene 35,175 diol lactone were treated by the technique delineatedin Example 11, thus producing correspondingly: 35-fiuoro-6-chloro-17a-(2'- carboxyethyl) A androsten 175 ol lactone, 35- fluoro 6 chloro 17a (2' -carboxyethy1) 19 -nor A 5 androsten 175 ol lactone, 313,6 -difiuoro 17a-(2'- carboxyethyl) 19 nor A androsten 17,8 o1 lactone and 35,6 difluoro 17cc (2' -carboxyethyl) A androsten-17fl-ol lactone.

Example IX In accordance with Example I, except that phosphorus pentachloride was substituted by phosphorus pentabrornide, there were treated: 17a-(2-carboXyethyl)-A -androstene-3B,17/3-diol lactone, 17u-(2-carboxyethyl)-19- nor-A -androstene-3B,17,8-diol lactone, 17zx-(2'-C8IbOXyvinyl)-l9-nor-A -androstene-3{3,17,8-diol lactone, and 170c- (2-carboxyvinyl)-A -androstene-3,8,17fi-dio1 lactone thus giving respectively: 3,8-brornol7u-(2-carboxyethyl)-A androsten-17fi-ol lactone, 3fi-bromo-17a-(2carboxyethyl)-l9-nor-A -androsten-17,8-01 lactone, 3fi-broino-l7a- (2'-carboxyviny1-19-nor-A -androsten-176-01 lactone, and 3fi-bromo 17a (2'-carboxyvinyl)-A -androsten-17fi-ol lactone.

Example X 1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; Y is selected from the group consisting of fluorine, chlorine and bromine and X is selected from the group consisting of fluorine and chlorine.

2. 36,6-dichl0ro 17a (2'-carboxyethyl) A androsten-17,8-ol-lact0ne.

wherein R is selected from the group consisting of hydrogen and methyl; Y is selected from the group consisting of fluorine, chlorine and bromine; and Z is selected from the group consisting of a double bond and a saturated linkage.

12. 3,8-chloro-17a-(2'-carboxyethyl) A androsten- 17,8-o1-lactone.

13. 3,Bfluoro-17a-(2 carboxyethyl) A androsten- 17B-o1-lactone.

14. 3,8-brorno-17a-(2' carboxyethyl) A androsten- 17,8-o1-lactone.

15. 3,8-fluoro-17a-(2-carboxyethy1 9 nor-M-androsten-17fl-ol-lactone.

16. 3,8-chloro-17a-(2 carboxyethyl) 19 nor-A androsten-17B-o1-lactone.

17. 3fi-fiuoro-17rx-(2 canboxyvinyl) A androsten- 17/9-o1-lactone.

18. 3fi-chloro-l7a-(2' carboxyvinyl) A androsten- 17B-o1-lactone.

19. 3,8-fluoro-17a-(2'-carboxyvinyl) 19 nor A -androsten-17;3-ol-lactone.

20. 3,B-chloro-17a-(2' carboxyvinyl) 19 nor-A -androsten-l7fi-ol-lact0ne.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 